ScienceDaily (July 12, 2012) — Readers of the scientific journals Science and Nature might have noticed a recent wave of articles, most recently in the July 13, 2012 issue of Science, with deep importance for biology and medicine. These papers, all published this year by collaborations headed by the Scripps Research Institute laboratory of Professor Raymond Stevens, illuminate a large and medically important family of proteins called G protein-coupled receptors (GPCRs).
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GPCRs sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters, and light. After binding these molecules, GPCRs trigger a specific response inside the cell. Many drugs, including allergy and heart medication and drugs for Parkinson's and Huntington's disease, target these proteins.
This year, a paper published January 19 (Liu et al., Science, 335, 1106) was quickly followed by related publications on the crystal structures of a lipid GPCR (Hanson et al., Science, 335, 851, February 17), the kappa opioid receptor (Wu et al., Nature, 485, 327, March 21), and the nociceptin opioid receptor (Thompson et al., Nature, 485, 395, May 17). The most recent publication is on the 1.8 angstrom high-resolution structure of the A2A adenosine receptor (Liu et al., Science, 336, 232, July 13) and is one of the highest resolution structures to date of a human membrane protein. The structure highlights the receptor and ligand as an allosteric machine controlled by sodium, water, cholesterol, and lipids.
These findings were made possible by technologies developed by the NIH Common Fund Joint Center for Innovative Membrane Technologies (JCIMPT) and the biological questions pursued by the GPCR Network, part of the Protein Structure Initiative:Biology at the National Institute for General Medical Sciences (NIGMS) in Bethesda, Maryland (NIGMS PSI:Biology).
Elusive GPCRs
The precise, three-dimensional arrangement of its constituent atoms is in some ways a protein's ultimate secret. Far more than its amino-acid sequence, the 3D structure holds the key to understanding how a protein interacts with its natural partner molecules in the body or with drug molecules.
But membrane protein structures are as hard to determine as they are valuable, and the most important structures, many of them GPCRs, have often been the most elusive. GPCRs are exceedingly flimsy, fragile proteins when not anchored within their native cell membranes. Coaxing them to line up to form crystals, so that their structures can be determined through X-ray crystallography, has been a formidable challenge for decades. For this reason, the NIH Common Fund highlighted membrane protein expression and stabilization technologies as a priority area of innovation and investment in 2004.
The first high-resolution human GPCR structure determined was the
See Also:
GPCRs sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters, and light. After binding these molecules, GPCRs trigger a specific response inside the cell. Many drugs, including allergy and heart medication and drugs for Parkinson's and Huntington's disease, target these proteins.
This year, a paper published January 19 (Liu et al., Science, 335, 1106) was quickly followed by related publications on the crystal structures of a lipid GPCR (Hanson et al., Science, 335, 851, February 17), the kappa opioid receptor (Wu et al., Nature, 485, 327, March 21), and the nociceptin opioid receptor (Thompson et al., Nature, 485, 395, May 17). The most recent publication is on the 1.8 angstrom high-resolution structure of the A2A adenosine receptor (Liu et al., Science, 336, 232, July 13) and is one of the highest resolution structures to date of a human membrane protein. The structure highlights the receptor and ligand as an allosteric machine controlled by sodium, water, cholesterol, and lipids.
These findings were made possible by technologies developed by the NIH Common Fund Joint Center for Innovative Membrane Technologies (JCIMPT) and the biological questions pursued by the GPCR Network, part of the Protein Structure Initiative:Biology at the National Institute for General Medical Sciences (NIGMS) in Bethesda, Maryland (NIGMS PSI:Biology).
Elusive GPCRs
The precise, three-dimensional arrangement of its constituent atoms is in some ways a protein's ultimate secret. Far more than its amino-acid sequence, the 3D structure holds the key to understanding how a protein interacts with its natural partner molecules in the body or with drug molecules.
But membrane protein structures are as hard to determine as they are valuable, and the most important structures, many of them GPCRs, have often been the most elusive. GPCRs are exceedingly flimsy, fragile proteins when not anchored within their native cell membranes. Coaxing them to line up to form crystals, so that their structures can be determined through X-ray crystallography, has been a formidable challenge for decades. For this reason, the NIH Common Fund highlighted membrane protein expression and stabilization technologies as a priority area of innovation and investment in 2004.
The first high-resolution human GPCR structure determined was the